Allogeneic bone marrow transplantation (alloBMT) has revolutionized the treatment of chronic myelogenous leukemia, the acute leukemias, and aplastic anemia (Champlin, 1993, Leukemia and Lymphoma 2:149–152; Rowe et al., 1994, Anal. Int. Med. 120:143–158). In alloBMT, a patient receives intensive myeloablative chemotherapy and/or radiotherapy followed by the infusion of bone marrow (BM) from a donor, usually a major histocompatibility complex (MHC) matched sibling or increasingly an MHC matched unrelated donor. Unfortunately, Graft-versus-Host Disease (GVHD), an alloimmune attack against host tissues, remains a morbid toxicity that greatly limits the applicability and efficacy of alloBMT in treatment of both malignant and inherited diseases (Ferrara et al., Eds., 1996, Graft vs. Host Disease, Marcel Dekker, Inc., NY). In GVHD, T cells react against a subset of host peptides bound to MHC molecules, called minor histocompatibility antigens, which are derived from expression of polymorphic genes that distinguish the host from donor. Severe GVHD is associated with a nearly four-fold risk of treatment failure in alloBMT for early leukemia and remains the major barrier preventing an expanded use of alloBMT in treatment of genetic diseases such as sickle cell anemia and thalassemia major (Horowitz et al., 1990, Blood 75:555–562; O'Marcaigh et al., 1997, Curr. Opinion in Oncol. 9:126–130; Lucarelli et al., 1997, Cancer treatment and Research 77:305–315; Gaziev et al., 1997, Transplantation 63:854–860). Efforts to understand the nature of GVHD effector cells and inflammatory cytokines released during GVHD reactions have not yet translated into approaches for managing clinical GVHD beyond immunosuppression directed largely against T cells.
Most T cell responses are initiated on so called “professional” antigen presenting cells (APCs). However, the roles of host and donor derived APCs in initiating GVHD have not been thoroughly examined. Further, targets for more specific GVHD therapy are at present unknown. The mechanism of antigen presentation to GVHD effector cells has been little studied and is not clearly understood (Korngold et al., 1983, Immunol. Rev. 71 5–29; Korngold et al., 1982, J. Exp. Med. 155:872–883). Antigen presentation in alloBMT is unique in that from the time the donor marrow cells are infused, both host and donor APCs could potentially stimulate T cells mediating GVHD. Since the BM of recipients is ablated by cytotoxic therapies prior to the transplant, one might assume that recipient APCs would not be available to initiate GVHD. Consistent with this reasoning, increasing the intensity of the ablative protocol does not reduce GVHD, but instead increases its severity (Truitt et al., 1991, Blood 77:2515–2523). On the other hand, since MHC Class I (MHC I) restricted CD8+ T cells play a central role in GVHD, one might suspect that recipient APCs would be required (Sprent et al., 1988, J. Exp. Med. 167:556–569; Korngold et al., 1987, Transplantation 44:335–339; Korngold et al., 1987, J. Exp. Med. 165:1552–1564). This is because on a given cell the peptide antigens presented by its MHC I molecules to CD8 T cells are derived largely from expression of genes within that cell. Donor derived APCs would therefore not have ready access to such host peptides as they do not express the host polymorphic genes that encode GVHD target antigens (Germain, 1994, Cell 76:287–299). However, recent data has demonstrated that extracellular antigens can be introduced into the MHC I antigen presentation pathway, a phenomenon dubbed “cross priming” (Matzinger et al., 1977, Cell. Immunol. 33:92–100; Bevan, 1976, J. Exp. Med. 143:1283–1288; Bevan, 1995, J. Exp. Med. 182:639–641; Carbone et al., 1989, Cold Spring Harbor Symp. Quant. Biol. 1:551–555; Huang et al., 1994, Science 264:961–965; Huang et al., 1996, Immunity 4:349–355; Srivastava et al., 1994, Immunogenetics 39:93–98; Arnold et al., 1995, J. Exp. Med. 182:885–889)
Experiments to date have not yet determined which source(s) of APCs, donor or host, are required for GVHD initiation. The resolution of this issue is of great practical as well as theoretical importance. Understanding the roles of donor and host APCs in GVHD induction will direct distinct and novel strategies for reducing GVHD by specifically targeting either population.
There is a long felt need in the art for the development of specific mechanisms for reducing GVHD in animals, particularly in humans. The present invention satisfies this need.